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588 J Neurol Neurosurg 2001;70:588–596 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.70.5.588 on 1 May 2001. Downloaded from as a of

P J de Vries, W G Honer, P M Kemp, P J McKenna

Abstract become clear that it is an oversimplification. Objectives—Cognitive impairment is Thus schizophrenic patients have been found to known to occur in schizophrenia, and may have a lower average IQ than the normal popu- be marked in institutionalised patients. lation,4 and to show wide ranging neuropsycho- The aim of this study was to determine logical test impairments, prominent among whether it ever warrants an additional which are deficits in and executive diagnosis of dementia. function.56 These deficits have been found in Methods—A population of chronic schizo- free78and never treated patients,9 and they phrenic patients who were aged 65 or are not easily attributable to poor , younger and showed no organic risk , and cooperation.10–13 factors for dementia were screened for It is also well established that institutional- presence of disorientation. Any showing ised schizophrenic patients, who have the most this underwent - severe and chronic forms of illness, sometimes ing, physical investigations, and struc- show more marked cognitive deficits which can tural and functional . be detected on the simple “bedside” tests of Information about day to day cognitive general knowledge, recall, copying, etc used to function was also obtained from carers. screen elderly patients for dementia.14–16 Up to Results—Eight patients aged 28 to 64 were 25% of such patients also show age disorienta- identified who showed disorientation; in tion, typically underestimating their age by a all cases this was accompanied by general margin of 5 years or more.17 This phenomenon intellectual impairment and objective evi- has been shown not to be a function of dence of a dementia . The pre-existing , prior physical patients’ schizophrenic symptoms were treatments, or institutionalisation, and it forms unexceptional and did not seem suYcient part of a wider pattern of cognitive impair- to account for their cognitive impairment. ment.18 19 Both global intellectual impairment Neuropsychological testing disclosed rela- and age disorientation increase in prevalence tive sparing of visual and visuospatial with advancing age in the population chroni- function and syntax, but perva- cally in hospital and become commonplace sive deficits in memory and executive over the age of 65.16 20 function. Brain CT demonstrated only In 1976 Marsden21 argued for the logical minor abnormalities but most of the extension of these findings, writing: “I have patients showed frontal or temporal hy- encountered a number of chronic schizo- poperfusion on SPECT. phrenic patients in whom full investigation has http://jnnp.bmj.com/ Conclusions—Dementia in schizophrenia revealed evidence of cognitive impairment and seems to be a real entity with a neuro- cerebral on air encephalography, psychological signature similar to that of Developmental whereas all other investigations for known Psychiatry Section, . Functional but causes of dementia have been negative.” Department of not structural imaging abnormalities may Nevertheless, despite this and occasional simi- Psychiatry, University also be characteristic. lar statements,22 23 dementia is not normally of Cambridge, UK (J Neurol Neurosurg Psychiatry 2001;70:588–596) considered to supervene in schizophrenia and

PJdeVries on September 27, 2021 by guest. Protected copyright. Keywords: schizophrenia; dementia; is not clearly recognised as a complication of University of British the disorder. Such a view also runs counter to Columbia, Vancouver, the prevailing beliefs that schizophrenic cogni- Canada As a “functional” , schizophrenia has, tive impairment is present premorbidly,24 25 is W G Honer from the beginning of the century, been neurodevelopmental in origin,26 and represents a “static ”.27 Finally, little is Department of distinguished from the “organic” psychoses of Nuclear Medicine, dementia and by the absence of any known about the pattern of neuropsychological Southampton General compromise of intellectual function.12 For impairment in severely cognitively impaired Hospital, UK example, in one of the original descriptions of schizophrenic patients and its correlates, if any, P M Kemp the disorder, Kraepelin3 stated that patients in structural and functional imaging. “remain surprisingly clear despite the most vio- Fulbourn Hospital, Cambridge CB1 5EF, lent excitement” and “often know accurately to UK a day how how long they have been in the insti- P J McKenna tution”. This distinction has stood the test of Methods time to the extent that acutely psychotic schizo- Patients with a clinical diagnosis of schizophre- Correspondence to: phrenic patients do not typically show disorien- nia in a large rehabilitation service catering Dr P J McKenna [email protected] tation, memory impairment, or other evidence mainly for chronic psychotic illness were infor- of cognitive failure, and were they to do so mally questioned about orientation in time, Received 3 May 2000 and in investigations would normally be undertaken to place, or person. Any showing evidence of final form 22 November 2000 exclude underlying neurological . disorientation were administered a more de- Accepted 8 December 2000 Nevertheless, over the past 20 years it has tailed orientation questionnaire previously

www.jnnp.com Dementia as a complication of schizophrenia 589 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.70.5.588 on 1 May 2001. Downloaded from

used in a study of institutionalised schizo- Patients over 40 also had ECG. Further inves- phrenic patients.18 This covers general orienta- tigations included autoimmune screen and tion, age orientation, elementary general white cell enzyme assay for metachromatic leu- knowledge, and knowledge about daily (for kodystrophy. Brain imaging included CT in all example, ward) routine. Only patients up to the cases, and MRI where indicated on the basis of age of 65 were included, to avoid the questionable CT findings. Tc 99m HMPAO prevalence of dementia due to organic disease single photon emission computed tomography above this age. Patients were excluded if they (SPECT) was carried out on seven patients had a history of head injury, neurological (one patient refused consent for this proce- disease, or any disease known to aVect brain dure). function, drug or misuse, or learning DSM-IV criteria for dementia additionally disability. History of known ischaemic heart require that the disturbance in cognitive disease, peripheral , or hyper- function cannot be better accounted for by tension were further exclusion criteria. Finally, another disorder such as schizophrenia. This any patients who gave absurd or delusional requirement may partly be in recognition of the responses—for example, stating their age to be fact that cognitive impairment is now accepted 200—were excluded from consideration. in schizophrenia, but it also reflects a long- Patients who made five or more errors on the standing belief that such impairment may orientation questionnaire were studied further sometimes be more apparent than real because to establish whether they met diagnostic crite- of the distracting eVects of symptoms, poor ria for dementia. According to ICD 10 and cooperation, or lack of motivation on perform- DSM-IV, this requires evidence of memory ance. To examine this issue, the patients’ symptoms were rated using the positive and impairment as well as multiple additional cog- 41 nitive impairments (for example, , negative syndrome scale (PANSS), a 30 item , , poor executive function) rating scale designed to assess the full range of in schizophrenia; the scale which impair social or occupational function- also contains an item rating disorientation. ing. There must also be evidence for a decline in cognition. Other CNS conditions have to be Results excluded. Eleven patients were identified who failed five Current intellectual level was assessed using or more items on the orientation questionnaire the Wechsler adult intelligence scale (WAIS) to but of these, only eight were cooperative measure IQ, plus the mini mental state enough to permit further investigation. Ages 28 examination (MMSE), a clinically oriented ranged from 27 to 64. All patients met cognitive screening test where a score of 23/24 DSM-IV criteria for schizophrenia, based on out of 30 has become widely used as a cut oV detailed clinical assessment and review of case 29 for dementia. To assess premorbid IQ, notes. All but one patient (see below) had educational achievement was determined, and unexceptional presentations of severe, chronic the national adult test (NART)30 was illness. The duration of illness was generally administered. This gives an estimate of best long, ranging from 9 to 30 years. Four of the level of IQ functioning based on ability to pro- patients were chronically in hospital, with the nounce irregular English words, and is rela- remainder being cared for at home by relatives http://jnnp.bmj.com/ tively resistant to the eVects of adult onset (one), living in sheltered accommodation dementing illness. A diVerence in WAIS IQ (two), or being treated on an acute psychiatric compared with NART estimated IQ of more ward having lived at home before admission than 15 points is widely used as a cut oV for (one). All patients were taking neuroleptic significant IQ decline.31 Specific neuropsycho- , but only one (patient 5) was taking logical tests covered standard areas of visual medication at the time of (subtests of the visual object and testing. One (patient 8) had had electroconvul- space perception battery (VOSP)32 and Rey sive therapy, but not in the preceding 12 on September 27, 2021 by guest. Protected copyright. figure copying33), language (the graded naming months. None of the patients had been treated test34 35 and the modified token test36), memory in the past with coma therapy. (the doors and people test37), and executive Figure 1 shows the eight patients’ orientation function (the modified Wisconsin card sorting scores in comparison with a sample of 120 test (WCST38), verbal fluency (number of ani- other rehabilitation patients with a clinical mals generated over 1 minute) and the cognitive estimates test39). Carers of the 55 patients were interviewed and completed a 50 45 Rest of sample questionnaire covering objective signs of de- 40 40 Disoriented patients mentia. Neuropsychological testing was car- 35 ried out with ethics committee permission, and 30 patients (and where possible their relatives) 25 gave consent for this and further investigations. 20 To exclude other CNS conditions, patients Patients (n) 15 underwent physical and neurological examina- 10 tion. Routine haematology and biochemistry 5 0 and chest radiography were performed, plus 20 19 18 17 16 15 14 13 12 11 10 987 standard screening investigations for dementia, Orientation score including thyroid function tests, red cell and Figure 1 Orientation scores for a sample of 128 chronic serum B12 and , and serology. schizophrenic patients.

www.jnnp.com 590 de Vries, Honer, Kemp, et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.70.5.588 on 1 May 2001. Downloaded from

diagnosis of schizophrenia who met the same of daily living skill failures typical of dementia inclusion and exclusion criteria. This sample in all patients; it is noteworthy that four was a subset of the patients in the service and patients were incontinent. was designed to encompass the range of sever- Six of the eight patients were age disoriented, ity encountered in chronic schizophrenia. It four underestimating their age by 4–8 years, was made up of all those who were chronically one overestimating it by 13 years, and one giv- in hospital or living in 24 hour staVed hostel ing a “don’t know” response. Some of these accommodation (n=63), plus a similar number patients underestimated the current year (four of patients who were able to live partially or patients) and the duration of their hospital stay fully independently (n=57). The vast majority (four patients), but there was never a clear pat- of patients made at most two errors, and the tern where temporal orientation errors were in eight disoriented patients were at the tail of a keeping with the patient’s subjective concept of distribution that was markedly skewed to the his or her own age. All the age disoriented left (the three further patients with orientation patients also failed non-temporal orientation scores of 15 or less were those mentioned above items. There was thus only limited support for who were not compliant enough to be tested). the view that schizophrenic disorientation has There were significantly more women in the its core in temporal disorientation or that “time disoriented patients than the comparison sam- stands still” for such patients, as has been sug- ple (men:women 3:5 60:30; p=0.035), but v gested.42 43 the two groups did not diVer significantly in The patients’ PANSS ratings for positive age (mean 46.6 v 43.5; NS) or years of educa- symptoms (, , and inco- tion (mean 11.6 v 11.8; NS). The eight patients’ educational backgrounds herence of speech), negative symptoms (lack of and cognitive status findings are summarised in volition, poverty of speech, and flattening of table 1. All had received primary and second- aVect), and general psychopathology (depres- ary education at normal schools; two had O sion, , catatonic symptoms, miscellane- levels and one had a university degree plus a ous psychotic symptoms, etc) are shown in fig- PhD. Two of the patients had become ill before ure 2, where they are compared with those of a leaving school; the rest had worked in normal large sample of 201 chronic schizophrenic 44 adult occupations. All patients showed multi- patients collected by one of us. As expected, ple orientation failures coupled with evidence the eight patients had disorientation ratings of global intellectual impairment. This was which were at or above the upper limit of those indicated either by MMSE scores below the cut for the sample as a whole. However, it is clear oV for dementia of 23/24 (six patients), or by that these high disorientation scores were not estimated premorbid current IQ discrepancies associated with corresponding high levels of of greater than 15 points (six patients), or both symptoms: positive symptoms and general psy- (four patients). Carer ratings showed evidence chopathology scores were unexceptional, and

Table 1 Background information and general intellectual measures in the patients

Education/best Duration of Orientation MMSE Estimated Current

Patient Sex Age occupation schizophrenia score Orientation failures score premorbid IQ IQ Carer ratings http://jnnp.bmj.com/ 1 Female 27 O levels 9 y 13/20 Duration of stay, day, 19/30 99 70 Memory diYculties Bank clerk season, place, cap. Italy Disorientation Gets lost DiYculty Incontinent

2 Female 31 Secondary school 17 y 7/20 Age, duration of stay, year, 20/30 95 56 Memory diYculties Never worked† day, month, PM, monarch cannot manage money Incontinent on September 27, 2021 by guest. Protected copyright. 3 Female 34 Secondary school 15 y 12/20 Age, duration of stay, 22/30 102 74 Memory diYculties Care assistant month, season, PM, cap. Disorientation Italy 4 Male 40 O levels 23 y 15/20 Age, season, duration of 24/30 113 68 Memory diYculties Never worked† stay, cap. Italy Disorientation

5 Male 56 Secondary school 25 y 11/20 Age, year, day, place, 21/30 92 77 Memory diYculties Draughtsman person, cap. Italy

6 Male 58 PhD 23 y 12/20 Age, year, place, PM, cap. 18/30 —* —* Memory diYculties Glass blower Italy Cannot carry out simple household tasks DiYculty dressing

7 Female 63 Secondary school 26 y 13/20 Age, year, duration of stay, 22/30 108 89 Memory diYculties Clerical work season, cap. Italy Cannot manage money DiYculty feeding Incontinent

8 Female 64 Secondary school 30 y 11/20 Duration of stay, day, 27/30 109 79 Memory diYculties Driver in armed season, place, monarch, Disorientation forces cap. Italy Cannot manage money DiYculty feeding self DiYculty dressing Doubly incontinent

*Patient’s first language not English. †Patient became ill before leaving school.

www.jnnp.com Dementia as a complication of schizophrenia 591 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.70.5.588 on 1 May 2001. Downloaded from

7 35 60 Table 3 Changes in cognitive performance of patient 7 over 6 years 6 30 55 5 1990–2 1996–7 50 4 25 General intellectual function: 45 MMSE 26 22 3 20 WAIS Full scale IQ 93 89 40 Verbal IQ 92 94 2 Performance IQ 93 84 15 1 35 Memory: Doors and people test 0 10 30 Verbal recall 19/36 10/36* Disorientation Positive Negative General Verbal recognition 18/24 10/24* Visual recall 12/36* 17/36* Figure 2 Patients’ scores on PANSS positive, negative, Visual recognition 14/24 9/24* and general psychopathology scales in comparison with a Executive function: sample of 201 chronic schizophrenic patients. WCST (categories achieved) 6 2* Verbal fluency (animals/1 min) 19 16 negative symptoms, although somewhat more Cognitive estimates test (error score) 6 15* marked, were not extreme. *Impaired using 5th percentile cutoV. Neuropsychological testing was carried out on seven patients (the first language of patient severe worsening, with auditory hallucinations 6 was not English, which would have aVected and catatonic symptoms which proved resistant his performance on many of the tests). The to all treatment; during the course of this, diso- findings are shown in table 2. There was a pat- rientation became evident for the first time. tern of scattered impairment on the tests of Severe intellectual impairment had been visual and visuospatial function, with the present for at least 10 years in three patients patients collectively failing nine of 35 tests. (patients 3, 4, and 7). Although patients 3 and Impairment was most frequent on tests requir- 4 showed a decline in IQ compared with ing planning (copying a complex figure) or premorbid estimates, they showed no obvious higher order (silhouette iden- progressive change in cognitive status over this tification). Performance on the language tests period. However, patient 7 had taken part in was patchy: there was relative preservation of neuropsychological studies 6 years previously. syntax (two of seven patients failing the modi- Her previous and current scores are shown in fied token test) coupled with more evidence of table 3: initially, her MMSE score was 26, in impairment in semantics (four of seven pa- the normal range, but this fell to 22, in the tients failing the graded naming test). demented range. Memory and executive per- By contrast, the patients failed almost all the formance also showed deterioration over the memory and executive tasks. Collectively, there same period: having initially been impaired on were failures on 30 out of 34 of these tests. In only one of four memory tests and none of many cases performance was drastically im- three executive tests, she became impaired on paired, as indicated by scores below the 1st all memory tests and and two out of three percentile or outside the normal range alto- executive tests. Nevertheless, her WAIS IQ did gether. not change over the period. The duration of the patients’ cognitive None of the patients showed abnormalities http://jnnp.bmj.com/ impairment was not usually easy to determine. on any of the laboratory investigations listed Onset of intellectual decline could be - above, with the exception of positive antinu- ably accurately dated in the one patient who clear antibodies in two patients. DNA binding did not have severe, chronic illness (patient 8). was normal in both these patients. No clinical She was a 64 year old married woman who had evidence of arteriopathy was present in any of had episodes of psychosis from the age of 34, the patients and only one patient showed ECG but who showed good recovery between abnormalities, which consisted of minor ST

episodes to the extent that she lived at home changes only. on September 27, 2021 by guest. Protected copyright. and carried out some household duties. Two Brain CT scans were reviewed with a neuro- years before examination she underwent a radiologist and the findings are summarised in

Table 2 Patients’ neuropsychological test scores

1234578 Visual function: VOSP Incomplete letters 19 19 20 19 19 18 19 VOSP Silhouettes 16 18 21 13* 11* 13* 15 VOSP Dot counting 8 10 10 9 10 8 9 VOSP Position discrimination 20 19 19 17* 20 20 6* Rey figure copy 25.5† 26† 35 25.5† 32 23 15† Language: Graded naming test (semantic) 9* 11* 13* 16 16 10* 14 Modified token test (syntax) 33 29* 31.5 32 30 30 25.5* Memory: Doors and people test combined verbal score 2† 6† 5† 0† 5† 7† 7† Doors and people test combined visual score 8† 1† 8* 2† 4† 5† b’line‡ Executive function: Modified WCST (categories achieved) 2† 2† 5 1† 2† 2† — Verbal fluency (animals/1 min.) 13* 15 9* 12* 9* 16 7† Cognitive estimates test (error score) 16† 26† 17† 15† 14* 15† 14*

*Below 5th percentile cutoV for normal. †Below 1st percentile or outside normal range altogether. ‡Based on score of 13/24 (=5th percentile) on visual recognition component of doors and people test only.

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Table 4 Structural and functional imaging findings

SPECT ratings of probable or definite Patient CT/MRI report Other CT findings SPECT report 1 Normal No change over 9 months. Equivocal R+L frontal hypoperfusion — 2 Normal — Not performed Not performed 3 Normal No change over 4 y Normal L+R temporal (4) 4 Normal/mild frontal atrophy* No change over 3 y Patchy perfusion R frontal and parietal regions L+R frontal (4) L+R parietal (5+4) 5 Normal No change over 2 y Bilateral frontal hypoperfusion L+R frontal (5) L+R temporal (4+5) L+R parietal (4+5) 6 Mild L temporal atrophy No change over 1 y Bilateral frontal hypoperfusion L+R frontal (5) 7 Cavum septum pellucidum+vergae. No changes over 3 y Not performed Not performed Possible lacunar infarct in L centrum semiovale 8 Generalised sulcal widening No change over 1 y Bilateral frontal and frontoparietal hypoperfusion L+R frontal (5) Small lucent area in L corona radiata L+R temporal (5)

*Based on diVerent reports of same CT.

7 7 6 A B C 6.5 6.5 5.5 6 6 5 5.5 5.5 4.5 5 5 4 4.5 4.5 3.5 4 4 2

Ventricular size Ventricular 3.5 3.5 2.5 3 Cortical sulcal size 3 2 2.5 2.5 Medial temporal atrophy 1.5 2 2 1 25–34 35–44 45–54 55–64 25–34 35–44 45–54 55–64 25–34 35–44 45–54 55–64 Age group (y) Figure 3 Patients’ lateral ventricular, sulcal, and medial temporal measures in relation to a sample of 251 schizophrenic patients. table 4. Clinically, the scans were reported as mean of ratings for temporal horn, suprasellar normal or showed only minor abnormalities, cistern, and temporal midbrain cistern); once which would not be expected to aVect cognitive again the eight patients’ scores are unremark- status—for example, cavum septum pelluci- able compared with the sample as a whole. dum. Further analysis was undertaken by two Brain SPECT was available for six patients independent raters using the CT rating scale (scanning was unsatisfactory due to movement for schizophrenia (CTRSS), an instrument artefact in patient 2 and patient 7 did not con- designed to quantify sulcal widening and sent to this procedure). As shown in table 4, the http://jnnp.bmj.com/ ventricular enlargement using a 1–7 scale for scans were reported clinically as abnormal in 11 separate regional measures.45 This scoring five, with frontal hypoperfusion or patchy system is reliable, minimally aVected by perfusion, plus parietal hypoperfusion in two variability in scanning procedures, and gives patients. To examine these findings further, the accurate estimates of sulcal and ventricular SPECT scans, together with scans of patients sizes based on the ranges found in a large data- with Alzheimer’s disease and healthy people, base of normal people and schizophrenic were reviewed blind by one of the authors patients. The approach is similar to the (PMK) who is a consultant in nuclear medi- on September 27, 2021 by guest. Protected copyright. CERAD neuroimaging protocol for demen- cine. Abnormalities were rated on a five point tia46; however, the range of reference photo- scale from normal (1) to unequivocally abnor- graphs in the CTRSS is scaled for a wider mal (5). Regions where there was probable range of age, but a narrower range of atrophy. (rating of 4) or definite (rating of 5) abnormal- Scores of 1 represent appearances in young ity are indicated in table 4. There was a pattern normal control subjects, scores of 7 represent of hypoperfusion which was variable across the those for elderly schizophrenic patients. sample, but which most often involved frontal The CTRSS measures for lateral ventricular and temporal regions. size and cortical sulcal widening are shown in figure 3, where they are plotted against a data- Discussion base of 251 schizophrenic patients with a simi- The patients in this case series not only had lar age range.45 It is evident that the changes fall schizophrenia, but also showed disorientation, well within the range seen in schizophrenia as a poor intellectual performance, and daily living whole. Paired t tests also failed to show signifi- skill failures up to and including incontinence, cant laterality diVerences in the patients’ sulcal features which would normally point to an or ventricular ratings. Atrophy of medial additional diagnosis of dementia. More rigor- temporal structures has been found to provide ous diagnostic requirements for dementia were a sensitive marker of Alzheimer’s disease.47–49 also met. The patients all had memory impair- Figure 3 therefore also shows ratings for the ment plus deficits in other areas of cognitive medial size (calculated as the function. They were all educationally normal

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before the onset of schizophrenia and most had cognitive deficits seen in schizophrenic patients worked as adults in jobs which required normal chronically in hospital18 56 and in any case can- intelligence. They all showed evidence of intel- not account for the findings of this study, as lectual decline from normal estimated IQ levels only half of the patients were in long stay hos- to low or even mentally handicapped levels of pital care. current IQ functioning. The only seeming dif- Neuroleptic medication, which all the pa- ference from the more familiar forms of tients had received for long periods, requires dementia was the lack of a progressive downhill more serious consideration as a cause of their course terminating in death. However, progres- cognitive impairment. There is a consensus sion is not intrinsically necessary to the defini- from many studies that neuroleptic have tion of dementia.50 Some —for at most minor deleterious eVects on neuro- example, those after head injury or psychological test performance in normal —are static, and others may show volunteers, and if anything they tend to only slow or imperceptible progression—for improve performance in schizophrenic pa- example, those complicating tients.57 58 The possibility that long exposure to and . these drugs could have a cumulative toxic eVect It seems unlikely that the patients in this on intellectual function has also been investi- study had known forms of dementia superim- gated: Owens and Johnstone14 reconstructed posed on schizophrenia. Tests for dementing the treatment records of 510 patients chroni- illnesses diagnosable in life were all negative. cally in hospital and found no relation between These included metachromatic intellectual test scores and lifetime neuroleptic which can sometimes present in late life.51 The exposure (or exposure to all other physical long duration of psychotic symptoms (9 to 30 treatments except insulin coma). It can also be years) also seems to preclude misdiagnosis of pointed out that age disorientation in schizo- some other neurological which can phrenia was first documented in the late 1950s, initially masquerade as schizophrenia but when neuroleptic treatment had not become ultimately declare themselves with appearance widespread or prolonged.17 42 of progressive dementia and neurological signs. Stevens et al17 identified correlates of age The coincidental development of Alzheimer’s disorientation in schizophrenia, including disease, multi-infarct dementia, or cortical young age of onset, long duration of illness, and disease in some of the older patients protracted inpatient stay. To some extent the is diYcult to exclude with certainty during life, patients in this study conformed to this and CT appearances may be deceptively pattern: they all had severe, intractable ill- normal in Alzheimer’s disease.52 However, nesses, most had a long duration, and some had there are for doubting that the patients become ill at a young or very young age. A fur- had any of these disorders: (a) Alzheimer’s dis- ther unexpected finding was an apparent ease is rare in the presenile period; (b) medial excess of female patients. Nevertheless, the temporal lobe atrophy was no greater in this present study can do no more than hint at series of patients than in schizophrenia as a clinical and demographic features associated whole; (c) multi-infarct dementia would be with dementia in schizophrenia, as the study unusual in the absence of other evidence of was small and did not employ a formal http://jnnp.bmj.com/ vascular disease; and (d) all three dementias case-control design. For the same reasons, it is would be likely to progress rather than remain not possible to be specific about the frequency static over periods of observation ranging from of dementia in schizophrenia. Although eight 2 to 10 years. One further dementia, fronto- patients (plus up to three more who were not temporal dementia, remains a realistic diVeren- investigated) could be found in a service tial diagnosis: this commonly presents in the containing about 200 chronic schizophrenic presenile period, may progress only slowly, and patients, such rates cannot be used to generate may show functional imaging abnormalities a prevalence figure without much more infor- coupled with structural imaging appearances mation about what leads patients to enter on September 27, 2021 by guest. Protected copyright. which remain normal for a long time.53–55 A rehabilitation services and how typical these counter argument, however, is that, on current patients were. evidence, psychotic symptoms are uncommon The fact that the patients in this series in frontotemporal dementia.55 showed severe intellectual deficits in the setting It is also unlikely that the eight patients’ of unremarkable levels of psychotic symptoms, disorientation and other signs of cognitive whereas other patients may show more severe impairment could be attributed to distraction symptoms without orientation being aVected, by psychotic symptoms, lack of motivation, suggests that schizophrenic cognitive impair- poor cooperation, etc. In general, such factors ment is an independent dimension of pathol- are no longer regarded as credible explanations ogy within the disorder. This is in keeping with of cognitive impairment in schizophrenia.56 the conclusion of several correlational and fac- Positive symptoms were not present in severe tor analytical studies of schizophrenia. These form in the patients, and whereas they did have found only weak associations between show relatively high levels of negative symp- neuropsychological test performance and over- toms, it would be diYcult to argue that poor all psychopathology,59 little or no association motivation could cause them to make errors on with delusions and hallucinations, some degree simple questions about orientation, or give rise of association with “disorganisation” symp- to a pattern of preserved performance on some toms (formal disorder and inappropri- tests but impairment on others. Institutionali- ate aVect), but a consistent association with sation is also discredited as a cause of the severe negative symptoms.60–63 These last correlations,

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although statistically significant, are typically structural brain abnormality. Clinical reports relatively low (of the order of 0.2–0.5), and it is suggested cortical atrophy only in three pa- clear that there is no one to one correspond- tients, where it was mild, and comparison ence between presence of negative symptoms against a database of schizophrenic CT scans and presence of cognitive impairment. indicated that all the patients fell within the The finding of levels of intellectual impair- range of modest lateral ventricular enlargement ment amounting to dementia in schizophrenia and cortical sulcal widening seen in the does not in any way contradict the evidence disorder as a whole.69 70 In general, CT70 and that poor cognitive performance is a feature of MRI71 studies have not yielded consistent the disorder which is sometimes present at evidence for a relation between cognitive onset964and may be detectable before this.24 25 impairment and structural abnormality in It merely suggests that in addition to such a schizophrenia. One study72 found that age “neurodevelopmental” pathology, there is a disoriented patients had postmorbid decline. Where our findings are at which were significantly larger than those who odds with the rest of the literature is that most were age oriented. However, another study22 73 studies have failed to show that schizophrenic found no correlation between lateral ventricu- cognitive impairment progresses from first lar size and either age disorientation or poor onset of illness, at least over the short term64 or performance. In our patients medium term.65 The evidence on long term there was also little to suggest progression of decline, however, is conflicting: for example, CT abnormalities over periods of time up to 10 Hyde et al66 found no progressive decline of years, further arguing against any direct MMSE scores across a group of schizophrenic relation between cognitive decline and progres- patients divided into diVerent age bands, but in sive loss of brain tissue. This is also in keeping a similar study Davidson et al16 found a linear with evidence from CT and MRI studies, decrease in MMSE scores with increasing age. which suggest that ventricular enlargement in At present there is no obvious way of recon- schizophrenia is present early in the course of ciling these contradictory findings; the paradox illness and does not progress, or at any rate not remains that some chronic schizophrenic to an easily detectable degree.74 patients show severe cognitive impairment The leading candidate for functional imag- which seems inherently unlikely to have been ing abnormality in schizophrenia, hypofrontal- present throughout life, but direct evidence of ity, has been found in only a minority of stud- deterioration during the acute or subacute ies under resting conditions.71 75 Although the stages of the disorder is lacking. It may be that evidence is stronger for an association between cognitive impairment in schizophrenia needs to and certain aspects of the be understood as following neither a strict schizophrenic clinical picture, such as negative neurodevelopmental trajectory—as seen for symptoms and chronicity, the findings for example in —nor the simple neurode- neuropsychological deficits are limited and generative course of a progressive dementia. In conflicting.71 The present study suggests that this vein, Dwork et al67 have speculated that a severe cognitive impairment in schizophrenia is subtle neuronal pathology in schizophrenia accompanied by resting functional imaging reduces the normal “” which abnormalities in the form of perfusion deficits protects against dementia and lowers the aVecting the frontal, temporal, and to a lesser http://jnnp.bmj.com/ threshold for the appearance of clinical cogni- extent parietal regions. These findings are pre- tive impairment. Such a process could be either liminary and limited by small numbers and neurodevelopmental, in which case it would lack of control data, but even so the rate of interact with the normal age related brain abnormality seems to be higher than that usu- degenerative changes to produce dementia at a ally found in schizophrenia—for example, in a higher rate than seen in the normal elderly study using SPECT and clinical ratings of per- population; or alternatively it might be slowly fusion deficits, Paulman et al76 found frontal progressive and eventually give rise to demen- hypoperfusion in 38% and 33% (left and on September 27, 2021 by guest. Protected copyright. tia by itself in a few cases. right), and temporal hypoperfusion in 33% and Neuropsychological testing of our severely 43%. cognitively impaired patients showed a pattern The state of severe cognitive impairment of predominant impairment in memory and evidenced by the patients in this study is clearly executive function coupled with relative spar- uncommon. However, such states seem to ing of visual and visuospatial function. When become frequent among elderly institutional- impairment was found on these tests, it ised schizophrenic patients, where up to two clustered in silhouette identification (which is thirds have been found to have MMSE scores sensitive to high level, semantic diYculties) and in the demented range.16 77 Postmortem studies copying of a complex figure (which may also be on such patients have shown that Alzheimer’s impaired in patients with lesions, disease is diagnosable in less than 10%, and thought to reflect poor planning). Language that there is no excess of multi-infarct demen- was aVected, where there were indications of tia, Lewy body disease, Pick’s pathology, or impairment in semantics coupled with relative markers for brain injury.67 78–81 These and other preservation of syntax. The overall pattern was findings led Harrison82 to state that elderly similar to that seen in schizophrenia generally56 schizophrenic patients with unequivocal, pro- and is indicative of predominant frontal and spectively assessed dementia show no evidence temporal lobe dysfunction.68 of any known neurodegenerative disorder. In this patient group clinical signs of demen- Clearly, dementia in schizophrenia requires a tia were not accompanied by any marked novel neuropathological explanation. Further

www.jnnp.com Dementia as a complication of schizophrenia 595 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.70.5.588 on 1 May 2001. Downloaded from

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